Blocking immunosuppressive neutrophils deters pY696-EZH2-driven brain metastases
- 27 May 2020
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science Translational Medicine
- Vol. 12 (545)
- https://doi.org/10.1126/scitranslmed.aaz5387
Abstract
The functions of immune cells in brain metastases are unclear because the brain has traditionally been considered "immune privileged." However, we found that a subgroup of immunosuppressive neutrophils is recruited into the brain, enabling brain metastasis development. In brain metastatic cells, enhancer of zeste homolog 2 (EZH2) is highly expressed and phosphorylated at tyrosine-696 (pY696)-EZH2 by nuclear-localized Src tyrosine kinase. Phosphorylation of EZH2 at Y696 changes its binding preference from histone H3 to RNA polymerase II, which consequently switches EZH2's function from a methyltransferase to a transcription factor that increases c-JUN expression. c-Jun up-regulates protumorigenic inflammatory cytokines, including granulocyte colony-stimulating factor (G-CSF), which recruits Arg1(+)- and PD-L1(+) immunosuppressive neutrophils into the brain to drive metastasis outgrowth. G-CSF-blocking antibodies or immune checkpoint blockade therapies combined with Src inhibitors impeded brain metastasis in multiple mouse models. These findings indicate that pY696-EZH2 can function as a methyltransferase-independent transcription factor to facilitate the brain infiltration of immunosuppressive neutrophils, which could be clinically targeted for brain metastasis treatment.Funding Information
- National Institutes of Health (R01 CA112567)
- National Institutes of Health (R01 CA184836)
- National Institutes of Health (R01 CA208213)
- National Institutes of Health (R21 CA223102)
- National Institutes of Health (P30 CA016672)
- Cancer Prevention and Research Institute of Texas (RP180734)
- Australian National Health and Medical Research Council grant (APP1113867)
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